Peripheral neuropathic pain is caused by trauma to the peripheral nervous system. The condition includes syndromes as diverse as diabetic neuropathy, cancer neuropathy, and trigeminal neuralgia. Neuropathic pain is largely resistant to treatment by current therapies. In the U.S. alone, as many as 3-4 million people suffer from neuropathic pain caused by diabetic neuropathy. Finding more effective treatments for these pain states represents an opportunity for producing substantial medical benefits and financial rewards. We have identified a novel class of Na+ channel antagonists that have promising activity in animal models of tonic and neuropathic pain. In Phase I we propose to synthesize >100 analogues of the initial lead and characterize these compounds electrophysiologically as antagonists of voltage-gated Na+ channels. Active compounds will be evaluated for anticonvulsant activity in rodents to give an initial estimate of bioavailability and 171 vivo activity. In Phase II we will extend the program to evaluate selected compounds in animal models of diabetic neuropathy and peripheral nerve trauma. The overall goal of this project is to design a Na+ channel antagonist that is specifically optimized for analgesic / anti-hyperalgesic activity, and to develop it for the treatment of neuropathic pain. PROPOSED COMMERCIAL APPLICATION: Novel voltage-gated Na+ channel antagonists have the potential to become useful drugs for the treatment of various forms of neuropathic pain for which no satisfactory therapies currently exist. In addition, they are also likely to be useful in the treatment of epilepsy.